Heart failure (HF) represents a final common pathway for both ischemic and non-ischemic cardiomyopathy, with an annual incidence >600,000 new cases each year, a disease prevalence >6 million patients, and an estimated annual cost >$30 billion in the USA alone. Improved understanding of HF pathophysiology throughout recent decades has led to critical advances in HF prognosis through neurohormonal blockade. Despite these improvements, the HF mortality rate remains extraordinarily high (>30% within 5 years of diagnosis) and HF remains the leading cause for hospitalization in patients >65 years (a growing segment of the US population). The HF epidemiologic data suggest that the current treatment paradigm fails to interrupt one or more key pathophysiologic mechanisms of HF, and confirm the urgent need to develop novel therapeutic approaches to alleviate symptoms of HF, improve quality of life, and reduce re-hospitalization for HF. The evidence supporting the presence of inflammation in HF is overwhelming. One of the unanswered questions is whether inflammation plays a key role in the progression of HF or is merely a marker of disease. Recent data from our group and others have shown that the systemic inflammatory response in patients with HF can be inhibited with the use of a targeted Interleukin-1 (IL-1) blockers, anakinra or canakinumab. Both in preclinical and clinical studies, in parallel with reducing systemic inflammation, IL-1 blockers preserved or restored cardiac function, whether the effects on systemic inflammation and on cardiac function are intertwined and cannot be dissociated, or whether they are independent has not been explored. IL-1 is a master regulator of the inflammatory response, namely NF-kB activation, that is shared with many other cytokines and is part of the redundancy of the system. An unconventional signaling of the IL-1 receptor signaling through the phosphoinositide-3 kinase ? (PI3K?) has been characterized in inflammation and cancer. Whether IL-1 signaling in HF is mediated through PI3K? remains unknown. We hypothesize that enhanced levels of IL-1 increase PI3K p110? expression in cardiomyocytes, that in turn results in selective induction of p87 co- signaling, and cardiac dysfunction through a scaffolding function on PDE3B. To test this hypothesis, we will determine whether IL-1 induces p110? and p87 in cardiomyocytes in vitro and in vivo (Aim #1); whether PI3K? mediates IL-1 induced systolic dysfunction in vivo (Aim #2); and whether we can distinguish the kinase- dependent from the scaffolding function of PI3K? in cardiac dysfunction (Aim #3). Determining the mechanisms by which inflammation, and IL-1 in specific, contributes to cardiac dysfunction may open the way to more and better ways to prevent and treat heart failure ? which is an urgent unmet need.